Pharmaceutical compositions are well known to have significant differences in solubility, oral absorption, drug activity, stability and the like depending on the kind and crystallized type of their salts, even when they are made of the same ingredient in free form. For the development of a pharmaceutical composition, it is therefore extremely important to select an ingredient enabling itself to fulfill the most preferred conditions, based on the results obtained by making comprehensive analysis on the material's characteristics, such as chemical stability, bioavailability and physical stability (the degree of crystallinity and the degree of hydration), effects on pharmaceutical properties (hardness, disintegration property and elution property) and effects on pharmaceutical capabilities (formability, anticaking property and capacity).
Piperazine derivatives, which are categorized into polyacidic basic compounds and represented typically by 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide, are useful as inhibitors against the enzyme (acyl coenzyme A cholesterol acyltransferase, ACAT) that catalyzes the synthesis of cholesterol into a cholesterol ester (WO 98/54153 Pamphlet).
Inhibition of ACAT is thought to prevent cholesterol absorption through the intestinal tract, and also to suppress the secretion of very-low-density lipoprotein into blood at the liver, leading to a reduction in blood cholesterol. Further, inhibition of ACAT suppresses the foaming of macrophages in artery walls, so atherosclerosis lesions are expected to shrink per se. ACAT inhibitors are, therefore, expected to be applicable for the treatment and prevention of various diseases such as hyperlipidemia, arteriosclerosis, cervical and cerebral arteriosclerosis, cerebrovascular accidents, ischemic heart diseases, coronary sclerosis, nephrosclerosis, arteriosclerotic nephrosclerosis, arteriolosclerotic nephrosclerosis, malignant nephrosclerosis, ischemic bowel diseases, acute mesenteric vaso-occlusion, chronic intestinal angina, ischemic colitis, aortic cancer, and arteriosclerosis obliterans (ASO), and numerous researches and developments are now under way.
Among the above-described piperazine derivatives useful as ACAT inhibitors, 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide, for example, has a problem such that it crystallizes in the form of the free base, but its oral absorption is little well because its crystals are not uniform and its physical stability and water solubility are too low.
Solutions to the aforementioned problems have been attempted mainly by adding an acid to such polyacidic basic compounds to improve their oral absorption or the like and using them as acid addition salts. For example, 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide can be substantially improved in water solubility and oral absorption by converting it into the tetrahydrochloride 2-water adduct with an excess amount of hydrochloric acid.
Nonetheless, it has been pointed out that the number of moles of the added acid affects the physical properties of the resulting acid addition salt of the polyacidic basic compound, and that the tetrahydrochloride 2-water adduct cannot avoid a low degree of crystallinity in its powder X-ray diffraction analysis; it is susceptible to dehydration and dehydrochlorination in a differential scanning thermal analysis; and it is also recognized as having high hygroscopicity in a hygroscopicity test. A further problem is also presumed in that tableting machines and aluminum sheets may undergo metal corrosion due to the residual of the acid used in excess and the strong acidity of the tetrahydrochloride. This raises concern about effects of the metal corrosion on the formulation of a pharmaceutical preparation and also on the stability of the pharmaceutical preparation. It is necessary to fully control factors such as drying temperature, vacuum (reduced pressured) level and drying degree upon preparation. Yet it is difficult to efficiently and stably supply such acid addition salts as active ingredients for pharmaceutical compositions while always providing them with uniform physical properties.
For the resolution of the above-described problems, it may be contemplated to prepare an acid addition salt with the number of moles of the acid to be added being controlled. However, there is still a problem in that when hydrochloric acid or the like is used as an acid, it is difficult to accurately measure the amount of the acid in a mole number desired to be added to 1 mole of a polyacidic basic compound, thereby becoming too hard to easily prepare the acid addition salt of the polyacidic basic compound, said salt containing the added acid in a desired number of moles, or a water adduct of the acid addition salt.
Accordingly, there has since been strong demand for a preparation method making it possible to easily adjust the number of moles of an acid in an acid addition salt of a polyacidic basic compound to a number suited for the polyacidic basic compound as needed.